Researchers at the University of Washington report in the May 15 Journal of Neuroscience (Volume 20, RC75) the first direct evidence in mice that
protein kinase A (PKA) signaling regulates both alcohol-seeking behavior and sensitivity to some of the effects of alcohol intoxication. Given a
choice between plain water and solutions containing alcohol, mice missing the RIIB subunit of PKA preferred the alcohol solution at its highest
strengths. In addition, the gene knockout mice were less sensitive than those with normal PKA to alcohol’s sedative effects.

A protein involved in intracellular communication, PKA is present throughout the brain. PKA phosphorylates numerous intracellular proteins and
regulates gene expression, thereby altering the electrical properties of the cell and, potentially, cell function and communication between
neurons. Mice missing RIIB, one of six genes that encode PKA, experience alterations in PKA activity, a condition the researchers believe alters
their response to the pharmacologic properties of alcohol.

"Earlier research in both laboratory cultures and animals indicated that alcohol consumption influences PKA function," said Enoch Gordis, M.D.,
Director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), which provided primary support for the study. "What is new about
this work is the reverse  that, at least in the animal model, PKA can regulate alcohol consumption and some aspects of alcohol response."

Todd Thiele, Ph.D., Department of Psychology and the Alcohol and Drug Abuse Institute, University of Washington, and his colleagues
examined drinking behavior in 12 normal mice and 12 knockout mice with a mutation in the RIIb subunit of PKA. Whereas no differences were
found between the two groups in taste preference for sweet or bitter solutions, mice with the PKA mutation drank nearly twice as much
20-percent alcohol solution as normal mice.

The researchers also measured the time needed for intoxicated mice to regain the righting reflex. They injected both groups of mice with alcohol
and then placed them on their backs in plastic U-shaped troughs. Knockout mice recovered much faster from the sedative effects of alcohol,
regaining their footing after 65 minutes compared with 90 minutes for the normal mice.

"It is likely that the mice with the RIIB mutation drink more ethanol because PKA activity is disrupted in brain regions involved with mediating
ethanol reward," said Dr. Thiele. "It is now important to determine in which brain regions the RIIB subunit produces these effects."

In addition to NIAAA, the National Institute of Neurological Disorders and Stroke, the National Institute of General Medical Sciences, and a
private donation provided support for the study.